tbuckley/cabot-search huggingface dataset:
Large-Scale Chromosomal Changes Lead to Genome-Level Expression Alterations, Environmental Adaptation, and Speciation in the Gayal (<i>Bos frontalis</i>)
Authors: Yan Li, Sheng Wang, Zhe Zhang, Jing Luo, Guo Liang Lin, Wei-Dong Deng, Zhifan Guo, Feng Ming Han, Li-Li Wang, Jie Li, Shi-Fang Wu, He-Qun Liu, Sheng He, Robert W Murphy, Zi-Jie Zhang, David N Cooper, Dong-Dong Wu, Ya-Ping Zhang
Journal: Molecular Biology and Evolution (2023)

Abstract Determining the functional consequences of karyotypic changes is invariably challenging because evolution tends to obscure many of its own footprints, such as accumulated mutations, recombination events, and demographic perturbations. Here, we describe the assembly of a chromosome-level reference genome of the gayal (Bos frontalis) thereby revealing the structure, at base-pair-level resolution, of a telo/acrocentric-to-telo/acrocentric Robertsonian translocation (2;28) (T/A-to-T/A rob[2;28]). The absence of any reduction in the recombination rate or genetic introgression within the fusion region of gayal served to challenge the long-standing view of a role for fusion-induced meiotic dysfunction in speciation. The disproportionate increase noted in the distant interactions across pro-chr2 and pro-chr28, and the change in open-chromatin accessibility following rob(2;28), may, however, have led to the various gene expression irregularities observed in the gayal. Indeed, we found that many muscle-related genes, located synthetically on pro-chr2 and pro-chr28, exhibited significant changes in expression. This, combined with genome-scale structural variants and expression alterations in genes involved in myofibril composition, may have driven the rapid sarcomere adaptation of gayal to its rugged mountain habitat. Our findings not only suggest that large-scale chromosomal changes can lead to alterations in genome-level expression, thereby promoting both adaptation and speciation, but also illuminate novel avenues for studying the relationship between karyotype evolution and speciation.
Single-molecule Sequencing of an Animal Mitochondrial Genome Reveals Chloroplast-like Architecture and Repeat-mediated Recombination
Authors: Joel Sharbrough, Laura Bankers, Emily Cook, Peter D Fields, Joseph Jalinsky, Kyle E McElroy, Maurine Neiman, John M Logsdon, Jeffrey L Boore
Journal: Molecular Biology and Evolution (2023)

Abstract Recent advances in long-read sequencing technology have allowed for single-molecule sequencing of entire mitochondrial genomes, opening the door for direct investigation of the mitochondrial genome architecture and recombination. We used PacBio sequencing to reassemble mitochondrial genomes from two species of New Zealand freshwater snails, Potamopyrgus antipodarum and Potamopyrgus estuarinus. These assemblies revealed a ∼1.7 kb structure within the mitochondrial genomes of both species that was previously undetected by an assembly of short reads and likely corresponding to a large noncoding region commonly present in the mitochondrial genomes. The overall architecture of these Potamopyrgus mitochondrial genomes is reminiscent of the chloroplast genomes of land plants, harboring a large single-copy (LSC) region and a small single-copy (SSC) region separated by a pair of inverted repeats (IRa and IRb). Individual sequencing reads that spanned across the Potamopyrgus IRa-SSC-IRb structure revealed the occurrence of a “flip-flop” recombination. We also detected evidence for two distinct IR haplotypes and recombination between them in wild-caught P. estuarinus, as well as extensive intermolecular recombination between single-nucleotide polymorphisms in the LSC region. The chloroplast-like architecture and repeat-mediated mitochondrial recombination we describe here raise fundamental questions regarding the origins and commonness of inverted repeats in cytoplasmic genomes and their role in mitochondrial genome evolution.
Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline
Authors: A. Falanga, C. Ay, M. Di Nisio, G. Gerotziafas, L. Jara-Palomares, F. Langer, R. Lecumberri, M. Mandala, A. Maraveyas, I. Pabinger, M. Sinn, K. Syrigos, A. Young, K. Jordan
Journal: Annals of Oncology (2023)
Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation
Authors: Sultan Tousif, Anand P. Singh, Prachi Umbarkar, Cristi Galindo, Nicholas Wheeler, Angelica Toro Cora, Qinkun Zhang, Sumanth D. Prabhu, Hind Lal
Journal: Circulation Research (2023)

The tyrosine kinase inhibitor ponatinib is the only treatment option for chronic myelogenous leukemia patients with T315I (gatekeeper) mutation. Pharmacovigilance analysis of Food and Drug Administration and World Health Organization datasets has revealed that ponatinib is the most cardiotoxic agent among all Food and Drug Administration-approved tyrosine kinase inhibitors in a real-world scenario. However, the mechanism of ponatinib-induced cardiotoxicity is unknown.
Single-cell transcriptomics reveals a mechanosensitive injury signaling pathway in early diabetic nephropathy
Authors: Shuya Liu, Yu Zhao, Shun Lu, Tianran Zhang, Maja T. Lindenmeyer, Viji Nair, Sydney E. Gies, Guochao Wu, Robert G. Nelson, Jan Czogalla, Hande Aypek, Stephanie Zielinski, Zhouning Liao, Melanie Schaper, Damian Fermin, Clemens D. Cohen, Denis Delic, Christian F. Krebs, Florian Grahammer, Thorsten Wiech, Matthias Kretzler, Catherine Meyer-Schwesinger, Stefan Bonn, Tobias B. Huber
Journal: Genome Medicine (2023)

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and histopathologic glomerular lesions are among the earliest structural alterations of DN. However, the signaling pathways that initiate these glomerular alterations are incompletely understood.To delineate the cellular and molecular basis for DN initiation, we performed single-cell and bulk RNA sequencing of renal cells from type 2 diabetes mice (BTBR ob/ob) at the early stage of DN.Analysis of differentially expressed genes revealed glucose-independent responses in glomerular cell types. The gene regulatory network upstream of glomerular cell programs suggested the activation of mechanosensitive transcriptional pathway MRTF-SRF predominantly taking place in mesangial cells. Importantly, activation of MRTF-SRF transcriptional pathway was also identified in DN glomeruli in independent patient cohort datasets. Furthermore, ex vivo kidney perfusion suggested that the regulation of MRTF-SRF is a common mechanism in response to glomerular hyperfiltration.Overall, our study presents a comprehensive single-cell transcriptomic landscape of early DN, highlighting mechanosensitive signaling pathways as novel targets of diabetic glomerulopathy.
Bridging deep sequencing to precision oncology in meningiomas
Authors: Xing Liu, Chunsheng Kang
Journal: Neuro-Oncology (2023)

Journal Article Bridging deep sequencing to precision oncology in meningiomas Get access Xing Liu, Xing Liu Department of Neuropathology, Beijing Neurosurgical Institute, Beijing, China Search for other works by this author on: Oxford Academic PubMed Google Scholar Chunsheng Kang Chunsheng Kang Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Key Laboratory of Post-Neuro Injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China Corresponding Author: Chunsheng Kang, Ph.D. and M.D., Laboratory of Neuro-oncology, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China (kang97061@tmu.edu.cn). https://orcid.org/0000-0002-3255-3369 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 3, March 2023, Pages 531–532, https://doi.org/10.1093/neuonc/noad004 Published: 10 January 2023 Article history Published: 10 January 2023 Corrected and typeset: 03 February 2023
Quality-of-life outcomes and risk prediction for patients randomized to nivolumab plus ipilimumab vs nivolumab on LungMAP-S1400I
Authors: Joseph M Unger, Lu Qian, Mary W Redman, Susan S Tavernier, Lori Minasian, Ellen V Sigal, Vassiliki A Papadimitrakopoulou, Michael Leblanc, Charles S Cleeland, Samuel A Dzingle, Thomas J Summers, Herta Chao, Sheshadri Madhusudhana, Liza Villaruz, Jeffrey Crawford, Jhanelle E Gray, Karen L Kelly, David R Gandara, Lyudmila Bazhenova, Roy S Herbst, Scott N Gettinger, Carol M Moinpour
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background An important issue for patients with cancer treated with novel therapeutics is how they weigh the effects of treatment on survival and quality of life (QOL). We compared QOL in patients enrolled to SWOG S1400I, a substudy of the LungMAP biomarker-driven master protocol. Methods SWOG S1400I was a randomized phase III trial comparing nivolumab plus ipilimumab vs nivolumab for treatment of immunotherapy-naïve disease in advanced squamous cell lung cancer. The primary endpoint was the MD Anderson Symptom Inventory–Lung Cancer severity score at week 7 and week 13 with a target difference of 1.0 points, assessed using multivariable linear regression. A composite risk model for progression-free and overall survival was derived using best-subset selection. Results Among 158 evaluable patients, median age was 67.6 years and most were male (66.5%). The adjusted MD Anderson Symptom Inventory–Lung Cancer severity score was 0.04 points (95% confidence interval [CI] = −0.44 to 0.51 points; P = .89) at week 7 and 0.12 points (95% CI = −0.41 to 0.65; P = .66) at week 13. A composite risk model showed that patients with high levels of appetite loss and shortness of breath had a threefold increased risk of progression or death (hazard ratio [HR] = 3.06, 95% CI = 1.88 to 4.98; P &amp;lt; .001) and that those with high levels of both appetite loss and work limitations had a fivefold increased risk of death (HR = 5.60, 95% CI = 3.27 to 9.57; P &amp;lt; .001)—compared with those with neither risk category. Conclusions We found no evidence of a benefit of ipilimumab added to nivolumab compared with nivolumab alone for QOL in S1400I. A risk model identified patients at high risk of poor survival, demonstrating the prognostic relevance of baseline patient-reported outcomes even in those with previously treated advanced cancer.
Extru-seq: a method for predicting genome-wide Cas9 off-target sites with advantages of both cell-based and in vitro approaches
Authors: Jeonghun Kwon, Minyoung Kim, Woochang Hwang, Anna Jo, Gue-Ho Hwang, Minhee Jung, Un Gi Kim, Gang Cui, Heonseok Kim, Joon-Ho Eom, Junho K. Hur, Junwon Lee, Youngho Kim, Jin-soo Kim, Sangsu Bae, Jungjoon K. Lee
Journal: Genome biology (2023)

We present a novel genome-wide off-target prediction method named Extru-seq and compare it with cell-based (GUIDE-seq), in vitro (Digenome-seq), and in silico methods using promiscuous guide RNAs with large numbers of valid off-target sites. Extru-seq demonstrates a high validation rate and retention of information about the intracellular environment, both beneficial characteristics of cell-based methods. Extru-seq also shows a low miss rate and could easily be performed in clinically relevant cell types with little optimization, which are major positive features of the in vitro methods. In summary, Extru-seq shows beneficial features of cell-based and in vitro methods.
Targeting Synovial Lymphatic Function as a Novel Therapeutic Intervention for <scp>Age‐Related</scp> Osteoarthritis in Mice
Authors: Xi Lin, Richard D. Bell, Sarah E. Catheline, Takahiro Takano, Andrew McDavid, Jennifer H. Jonason, Edward M. Schwarz, Lianping Xing
Journal: Arthritis & Rheumatology (2023)

The synovial lymphatic system (SLS) removes catabolic factors from the joint. Vascular endothelial growth factor C (VEGF-C) and its receptor, VEGFR-3, are crucial for lymphangiogenesis. However, their involvement in age-related osteoarthritis (OA) is unknown. This study was undertaken to determine whether the SLS and the VEGF-C/VEGFR-3 pathway contribute to the development and progression of age-related OA, using a murine model of naturally occurring joint disease.
Pulmonary Mucormycosis with Rib Involvement in an Immunocompromised Patient
Authors: Yan Liu, Jiuyang Xu, Chunlei Wang, Binghuai Lu, Chaoyang Liang, Gang Hou, Xiaojing Cui, Bin Cao
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Pulmonary Mucorcycosis with Rib Involvement in an Immunocompromised Patient." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Tumor-infiltrating lymphocytes mediate complete and durable remission in a patient with NY-ESO-1 expressing prostate cancer
Authors: Julia Karbach, Dragan Kiselicki, Kathrin Brand, Claudia Wahle, Evgueni Sinelnikov, Dirk Gustavus, Hans Hoffmeister, Hans-Bernd Prisack, Akin Atmaca, Elke Jäger
Journal: Journal for ImmunoTherapy of Cancer (2023)

Adoptive transfer of autologous tumor-specific lymphocytes represents a viable treatment method for patients with advanced malignancies. Here, we report a patient's case with metastatic hormone-refractory New York esophageal squamous cell carcinoma 1 (NY-ESO-1) expressing prostate cancer treated with in vitro expanded tumor-infiltrating lymphocytes (TILs) in conjunction with IL-2 and immune-checkpoint blockade. Complete and durable tumor remission was observed after three TIL infusions consisting of 1.4×109, 2.0×109, and 8.0×109 T cells, respectively, lasting now for more than 3.5 years. Immunological correlates to the clinical development were the decrease of tumor-driven NY-ESO-1 serum antibody and the drop of prostate-specific antigen to <0.01 µg/L. TILs were reactive against cancer-testis antigen NY-ESO-1, individual tumor mutational proteins (eg, PRPF8, TRPS1), and the androgen receptor splice variant 12.
New prognostic model in patients with advanced urothelial carcinoma treated with second-line immune checkpoint inhibitors
Authors: Aristotelis Bamias, Axel Merseburger, Yohann Loriot, Nicholas James, Ernest Choy, Daniel Castellano, F Lopez-Rios, Fabio Calabrò, Mario Kramer, Guillermo de Velasco, Roubini Zakopoulou, Kimon Tzannis, Cora N Sternberg
Journal: Journal for ImmunoTherapy of Cancer (2023)

Bellmunt Risk Score, based on Eastern Cooperative Oncology Group (ECOG) performance status (PS), hemoglobin levels and presence of liver metastases, is the most established prognostic algorithm for patients with advanced urothelial cancer (aUC) progressing after platinum-based chemotherapy. Nevertheless, existing algorithms may not be sufficient following the introduction of immunotherapy. Our aim was to develop an improved prognostic model in patients receiving second-line atezolizumab for aUC.
Novel role of microphthalmia-associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid-derived suppressor cells
Authors: Aram Lee, Haesun Park, Soyoung Lim, Jihyun Lim, Jaemoon Koh, Yoon Kyung Jeon, Young Yang, Myeong-Sok Lee, Jong-Seok Lim
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Microphthalmia-associated transcription factor (MITF) is a master regulator of melanogenesis and is mainly expressed in melanoma cells. MITF has also been reported to be expressed in non-pigmented cells, such as osteoclasts, mast cells, and B cells. However, the roles of MITF in immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), remain unclear. Here, we investigated the role of MITF in the differentiation process of MDSCs during tumor development. Methods In vitro-generated murine MDSCs and primary MDSCs from breast cancer-bearing mice or lung carcinoma-bearing mice were used to determine the expression level of MITF and the activity of MDSCs. Additionally, we investigated whether in vivo tumor growth can be differentially regulated by coinjection of MDSCs in which MITF expression is modulated by small molecules. Furthermore, the number of MITF + monocytic (MO)-MDSCs was examined in human tumor tissues or tumor-free lymph nodes by immunohistochemistry (IHC). Results The expression of MITF was strongly increased in MO-MDSCs from tumors of breast cancer-bearing mice compared with polymorphonuclear MDSCs. We found that MITF expression in MDSCs was markedly induced in the tumor microenvironment (TME) and related to the functional activity of MDSCs. MITF overexpression in myeloid cells increased the expression of MDSC activity markers and effectively inhibited T-cell proliferation compared with those of control MDSCs, whereas shRNA-mediated knockdown of MITF in myeloid cells altered the immunosuppressive function of MDSCs. Modulation of MITF expression by small molecules affected the differentiation and immunosuppressive function of MDSCs. While increased MITF expression in MDSCs promoted breast cancer progression and CD4 + or CD8 + T-cell dysfunction, decreased MITF expression in MDSCs suppressed tumor progression and enhanced T-cell activation. Furthermore, IHC staining of human tumor tissues revealed that MITF + MO-MDSCs are more frequently observed in tumor tissues than in tumor-free draining lymph nodes obtained from patients with cancer. Conclusions Our results indicate that MITF regulates the differentiation and function of MDSCs and can be a novel therapeutic target for modulating MDSC activity in immunosuppressive TMEs.
Dietary essential amino acids for the treatment of heart failure with reduced ejection fraction
Authors: Maurizio Ragni, Carolina Magdalen Greco, Arianna Felicetta, Shuxun Vincent Ren, Paolo Kunderfranco, Chiara Ruocco, Pierluigi Carullo, Veronica Larcher, Laura Tedesco, Ilenia Severi, Antonio Giordano, Saverio Cinti, Alessandra Valerio, Haipeng Sun, Yibin Wang, Chen Gao, Gianluigi Condorelli, Enzo Nisoli
Journal: Cardiovascular Research (2023)

Abstract Aims Heart failure with reduced ejection fraction (HFrEF) is a leading cause of mortality worldwide, requiring novel therapeutic and lifestyle interventions. Metabolic alterations and energy production deficit are hallmarks and thereby promising therapeutic targets for this complex clinical syndrome. We aim to study the molecular mechanisms and effects on cardiac function in rodents with HFrEF of a designer diet in which free essential amino acids—in specifically designed percentages—substituted for protein. Methods and results Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricle (LV) pressure overload or sham surgery. Whole-body glucose homeostasis was studied with glucose tolerance test, while myocardial dysfunction and fibrosis were measured with echocardiogram and histological analysis. Mitochondrial bioenergetics and morphology were investigated with oxygen consumption rate measurement and electron microscopy evaluation. Circulating and cardiac non-targeted metabolite profiles were analyzed by ultrahigh performance liquid chromatography-tandem mass spectroscopy, while RNA-sequencing was used to identify signalling pathways mainly affected. The amino acid-substituted diet shows remarkable preventive and therapeutic effects. This dietary approach corrects the whole-body glucose metabolism and restores the unbalanced metabolic substrate usage—by improving mitochondrial fuel oxidation—in the failing heart. In particular, biochemical, molecular, and genetic approaches suggest that renormalization of branched-chain amino acid oxidation in cardiac tissue, which is suppressed in HFrEF, plays a relevant role. Beyond the changes of systemic metabolism, cell-autonomous processes may explain at least in part the diet’s cardioprotective impact. Conclusion Collectively, these results suggest that manipulation of dietary amino acids, and especially essential amino acids, is a potential adjuvant therapeutic strategy to treat systolic dysfunction and HFrEF in humans.
Rare germline <i>complement factor H</i> variants in patients with paroxysmal nocturnal hemoglobinuria
Authors: Pedro Henrique Prata, Jacques-Emmanuel Galimard, Flore Sicre de Fontbrune, Anna Duval, Paula Vieira Martins, Stephane Roncelin, Pierre-Édouard Debureaux, Anne-Claire Lepretre, Lise Larcher, Rudy Birsen, Ygal Benhamou, Jean Soulier, Gérard Socié, Véronique Fremeaux-Bacchi, Régis Peffault de Latour
Journal: Blood (2023)
Abstract 1346: Rac1 GTPase Activtiy is Associated with Atrial Fibrosis and Fibrillation
Authors: Oliver Adam, Daniel Lavall, Hans-Joachim Schäfers, Michael Böhm, Ulrich Laufs
Journal: Circulation (2007)

Patients with atrial fibrillation (AF) are characterized by increased atrial fibrosis. The underlying signal transduction is incompletely understood. We hypothesized that activation of Rac1 GTPase contributes to increased fibrosis and atrial fibrillation via activation of NADPH oxidase and production of reactive oxygen species. Methods and Results: Samples of the left atrial appendage were analyzed in 8 patients with AF undergoing mitral valve surgery and 7 patients with sinus rhythm (SR) matched for atrial diameter. Despite same size of the atria, collagen content was significantly higher in AF compared to SR (14.9±2.1% vs. 8.5±1.3%). Expression analysis showed that AF was associated with upregulation of connective tissue growth factor (CTGF). Atria of patients with AF were characterized by significant upregulation of Rac1 total protein expression (Western blot), Rac1 activity (PAK pull-down assays) and a 20-fold upregulation of NADPH oxidase activity compared to SR (2225±500%). In order to test whether Rac1 plays a causal role in the pathogenesis in AF, transgenic mice with cardiac overexpres-sion (αMHC promoter) of Rac1 (RacET) were compared to wildtype (WT) and WT undergoing transaortic constriction (TAC, 360 μm). After 16 months, echocardiography showed similar left ventricular hypertrophy in RacET and TAC. RacET but not TAC exhibited atrial enlargement; 75% of RacET but no WT or TAC showed AF. Interstitial collagen content was significantly increased in the atria of RacET (44±1% of area vs 19±5% in WT). In contrast, interstitial fibrosis in TAC atria did not significantly differ from WT (31±6%). In the left ventricle, both RacET and TAC mice showed an elevated collagen content compared to the control group (WT 9±2%, RacET 29±3%; TAC 24±4%). In all mice, atrial collagen content exceeded ventricular collagen. All effects are significant with p&lt;0.05. Conclusion: Left atria of patients with AF exhibit upregulation of Rac1, increased NADPH oxidase activity and interstitial fibrosis. Cardiac-specific overexpression of Rac1 in mice results atrial fibrosis and fibrillation independent of left ventricular hypertrophy. Rac1-GTPase mediated activation of left atrial NADPH-oxidase may represent a novel target for the prevention of atrial fibrosis.